Hyperglycemia during critical illness is an independent risk factor for increased morbidity and mortality in adults and children, and tight glycemic control improves clinical outcomes in some adult intensive care unit (ICU) populations. There are currently no definitive outcome studies regarding glycemic control in critically ill children, and the adoption or even acceptance of regular approaches to glycemic control has not permeated pediatric critical care as it has in adult ICUs. In fact, routine glycemic control is quite rare in pediatric ICU practice. However, our pediatric critical care group at Emory University is one of the exceptions. While glycemic control is not currently considered standard care in pediatrics in any ICU, physicians at our center do choose to practice this intervention in critically ill children based on the positive effects illustrated by adult literature. However, to improve consistency and safety of our practice, we developed and implemented a pediatric-specific approach to strict glycemic control in our patients. We have determined that our protocol appears to be an efficient means to maintain our target blood glucose levels of 80-140 mg/dL without increasing rates of hypoglycemia. We have been practicing glycemic control in our pediatric ICU for 3 years using this protocol, and we believe that due to our unique experience and expertise in this field, we are now well-poised to conduct further much needed studies regarding glycemic control in children. To specifically address the void of knowledge regarding glycemic control in critically ill children, we propose a single-center randomized controlled trial to ascertain whether there is vital organ system, outcome, and resource utilization benefit to strict glycemic control vs. more conservative control in children requiring intensive care. The "Ped-E-Trol" ("Pediatric ICUs at Emory Glycemic Control) Trial will study 1,004 children admitted to the ICU for medical, surgical, or cardiac conditions requiring mechanical ventilation and/or vasopressor support who develop hyperglycemia, defined as persistent blood glucose >140 mg/dL). Participants will be randomized to either receive strict glycemic control (80-140 mg/dL) or more conservative control (190-220 mg/dL). Insulin infusions will be used to maintain blood glucose in these ranges. In addition to assessing organ and outcome specific efficacy parameters, we will meticulously evaluate for untoward effects including hypoglycemia, and determine the impact of this practice on costly medical resources. At the conclusion of this study we will determine if strict glycemic control (1) facilitates the recovery of function of select and composite organs affected by critical illness, (2) is a safe therapy without undo side effects and risks, and (3) lessens the requirement of hospital and intensive care support measures. Therefore, this project will begin to support, or rebuke, whether routine, strict glycemic control should be instituted as standard management in multi-disciplinary pediatric intensive care settings and provide the needed foundation for more focused and/or wider reaching multi-center trials on this topic in pediatric critical care. PUBLIC HEALTH RELEVANCE: The primary goal of this project is to determine whether normalizing hyperglycemia is a safe approach to improve multisystem organ function in critically ill children requiring intensive care. In adults with many forms of critical illness, the control of hyperglycemia improves outcomes including survival;yet to date there has been no definitive evaluation of this approach in pediatric critical care on which to base practice recommendations. We will draw on our unique experience of practicing routine glycemic control to conduct the "Ped-E-Trol" (the "Pediatric ICUs at Emory Glycemic Control) Trial, a 4-year single-center, prospective, randomized clinical trial to evaluate the outcome benefit, safety and resource utilization impact of maintaining strict glucose control in children with life-threatening conditions.